Reduced content of connexin43 gap junctions in ventricular myocardium from hypertrophied and ischemic human hearts.

TLDR

Gap junctions govern myocardial conduction, and their disturbance can underlie arrhythmia and mechanical inefficiency in ischemic and hypertrophied hearts. This study aimed to map gap junction organization in normal human ventricular myocardium and to determine whether chronic ischemia or hypertrophy alters this architecture. Connexin43 immunostaining and confocal microscopy were applied to surgical ventricular samples to quantify gap‑junctional surface area and distribution in normal and diseased hearts. Normal left ventricular myocardium exhibited a gap‑junctional surface area of 0.0051 µm²/µm³ (~11.6 junctions per cell), whereas ischemic and hypertrophied hearts showed reduced areas of 0.0027 and 0.0031 µm²/µm³ respectively, indicating diminished junctional content that may impair impulse propagation.

Abstract

BACKGROUND Gap junctions are a determinant of myocardial conduction. Disturbances of gap-junctional content may account for abnormalities of impulse propagation, contributing to the arrhythmic tendency and mechanical inefficiency of ischemic and hypertrophied myocardium. The aim of this study was to characterize gap junction organization in normal human ventricular myocardium and to establish whether abnormalities exist in myocardium of chronically ischemic and hypertrophied hearts. METHODS AND RESULTS Cardiac gap-junctional connexin43 antibodies and confocal microscopy were used in a quantitative immunohistochemical study of surgical myocardial samples to explore the structural basis of electromechanical ventricular dysfunction in chronic ischemic and hypertrophic heart diseases. Normal adult human left ventricular myocardium had a gap-junctional surface area of 0.0051 micron2/micron3 myocyte volume; gap junctions were confined to intercalated disks, of which there was a mean of 11.6 per cell. The right ventricle showed similar gap junction surface area. Left ventricular myocardium from ischemic hearts (distant from any fibrotic scarring), despite normal numbers of intercalated disks per cell, had a reduced gap junction surface area (0.0027 micron2/micron3; P = .02), as did hypertrophied myocardium (0.0031 micron2/micron3; P = .05). The cardiac myocytes in the pathological tissues were larger than normal, and estimated gap-junctional content per cell was reduced in ischemic ventricle (P = .02) compared with normal. CONCLUSIONS Gap junctions in normal adult human working ventricular myocardium occupy an area of 0.0051 micron2/micron3 myocyte volume. This surface area is reduced in ventricular myocardium from hearts subject to chronic hypertrophy and ischemia, despite a normal number of intercellular abutments, and this alteration may contribute to abnormal impulse propagation in these hearts.